In Vitro Hepatic Metabolism Explains Higher Clearance of Voriconazole in Children versus Adults: Role of CYP2C19 and Flavin-Containing Monooxygenase 3

Voriconazole is a broad spectrum antifungal agent for treating life-threatening fungal infections. Its clearance is approximately 3-fold higher in children compared with adults. Voriconazole is cleared predominantly via hepatic metabolism in adults, mainly by CYP3A4, CYP2C19, and flavin-containing monooxygenase 3 (FMO3). In vitro metabolism of voriconazole by liver microsomes prepared from pediatric and adult tissues (n = 6/group) mirrored the in vivo clearance differences in children versus adults, and it showed that the oxidative metabolism was significantly faster in children compared with adults as indicated by the in vitro half-life (T1/2) of 33.8 ± 15.3 versus 72.6 ± 23.7 min, respectively. The Km for voriconazole metabolism to N-oxide, the major metabolite formed in humans, by liver microsomes from children and adults was similar (11 ± 5.2 versus 9.3 ± 3.6 μM, respectively). In contrast, apparent Vmax was approximately 3-fold higher in children compared with adults (120.5 ± 99.9 versus 40 ± 13.9 pmol/min/mg). The calculated in vivo clearance from in vitro data was found to be approximately 80% of the observed plasma clearance values in both populations. Metabolism studies in which CYP3A4, CYP2C19, or FMO was selectively inhibited provided evidence that contribution of CYP2C19 and FMO toward voriconazole N-oxidation was much greater in children than in adults, whereas CYP3A4 played a larger role in adults. Although expression of CYP2C19 and FMO3 is not significantly different in children versus adults, these enzymes seem to contribute to higher metabolic clearance of voriconazole in children versus adults.

[1]  S. Björkman.  Prediction of Cytochrome P450-Mediated Hepatic Drug Clearance in Neonates, Infants and Children , 2012, Clinical pharmacokinetics.

[2]  Mats O. Karlsson,et al.  Population Pharmacokinetic Analysis of Voriconazole Plasma Concentration Data from Pediatric Studies , 2008, Antimicrobial Agents and Chemotherapy.

[3]  M. Kennedy.  Hormonal Regulation of Hepatic Drug‐Metabolizing Enzyme Activity During Adolescence , 2008, Clinical pharmacology and therapeutics.

[4]  D. Benjamin,et al.  Role of Flavin-Containing Monooxygenase in Oxidative Metabolism of Voriconazole by Human Liver Microsomes , 2008, Drug Metabolism and Disposition.

[5]  P. McNamara,et al.  Using ontogeny information to build predictive models for drug elimination. , 2008, Drug discovery today.

[6]  U. Christians,et al.  Pharmacokinetics of Mycophenolate Mofetil and Sirolimus in Children , 2008, Therapeutic drug monitoring.

[7]  M. Shimizu,et al.  Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes. , 2007, Biochemical pharmacology.

[8]  R. Herbrecht,et al.  Clinical pharmacokinetics of voriconazole. , 2006, International journal of antimicrobial agents.

[9]  G. Koren,et al.  Ontogeny of drug elimination by the human kidney , 2006, Pediatric Nephrology.

[10]  D. Benjamin,et al.  New antifungal agents under development in children and neonates , 2005, Current opinion in infectious diseases.

[11]  Sven Björkman,et al.  Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs. , 2005, British journal of clinical pharmacology.

[12]  M. Karlsson,et al.  Pharmacokinetics and Safety of Intravenous Voriconazole in Children after Single- or Multiple-Dose Administration , 2004, Antimicrobial Agents and Chemotherapy.

[13]  Susan M Abdel-Rahman,et al.  Developmental pharmacology--drug disposition, action, and therapy in infants and children. , 2003, The New England journal of medicine.

[14]  N. Wood,et al.  The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[15]  D A Smith,et al.  Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[16]  N. Wood,et al.  Pharmacokinetics and Safety of Voriconazole following Intravenous- to Oral-Dose Escalation Regimens , 2002, Antimicrobial Agents and Chemotherapy.

[17]  R. Obach,et al.  Measurement of Michaelis constants for cytochrome P450-mediated biotransformation reactions using a substrate depletion approach. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[18]  D. G. McCarver,et al.  The ontogeny of human drug-metabolizing enzymes: phase I oxidative enzymes. , 2002, The Journal of pharmacology and experimental therapeutics.

[19]  H. Yamazaki,et al.  Prediction of human liver microsomal oxidations of 7-ethoxycoumarin and chlorzoxazone with kinetic parameters of recombinant cytochrome P-450 enzymes. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[20]  H. Derendorf,et al.  Pharmacokinetic/Pharmacodynamic Profile of Posaconazole , 2010, Clinical pharmacokinetics.

[21]  H. Derendorf,et al.  Pharmacokinetic/Pharmacodynamic Profile of Voriconazole , 2006, Clinical pharmacokinetics.

[22]  Walter Schmitt,et al.  A Mechanistic Approach for the Scaling of Clearance in Children , 2006, Clinical pharmacokinetics.

[23]  Amin Rostami-Hodjegan,et al.  Prediction of the Clearance of Eleven Drugs and Associated Variability in Neonates, Infants and Children , 2006, Clinical pharmacokinetics.

[24]  C. Faure,et al.  Pharmacokinetics of Proton Pump Inhibitors in Children , 2005, Clinical pharmacokinetics.